Summary Retinal degeneration and related diseases are the leading cause of blindness and represent a major public health burden with economical and social impacts. As photoreceptor loss, the development of secondary vascular pathology causes disastrous consequences for vision. There is no effective treatment available. Our recent study revealed that a single intravenous injection of bone marrow derived mesenchymal stem cells (MSCs) at early stages of degeneration can preserve photoreceptors from death, sustain visual function, and limit pathological vascular changes in a rodent model of retinal degeneration. We propose to develop a treatment protocol that preserves vision and limits vascular pathology using non-invasive stem cell therapy in rodent models for retinal degeneration. We hypothesize that systemic administration of MSCs to treat ongoing retinal degeneration will slow the progress of photoreceptor loss and stabilize/repair the secondary vascular pathology by promoting the release of paracrine and autocrine mediators. The following specific aims are proposed: (1) Determine dose-response and long-term safety and efficacy of MSC treatment at early stages of degeneration in the RCS rat; (2) Investigate the neuro-vascular protective effects of MSCs at later stages of degeneration in the RCS rat and in Elovl4 mouse; (3) Examine the molecular mechanism of MSC homing to the retina and efficacy after intravenous administration. Based on the current extensive clinical experience using MSCs as therapy for both regenerative and degenerative medicine, if positive results are obtained in animal models, this treatment has a realistic likelihood of translation to the clinic.